Design,synthesis and antitumor activity of 3,6-disubstituted imidazo[1,2-a]pyrimidines as MNK inhibitors
Based on pyrido[3,2-d]pyrimidine derivatives with MNK inhibitory activity,a series of imidazo[1,2-a]pyrimidine derivatives were designed and synthesized via a scaffold hopping strategy.The key intermediate 6-bromoimidazo[1,2-a]pyrimidine was obtained from 5-bromopyrimidine-2-amine,and the target compounds 8a-8x were obtained through Suzuki coupling,iodination,amidation reaction,etc.The inhibitory rate of the target compounds against MNKs at 1 μmol·L-1 was measured by HTRF method,and the antiproliferation activity of the target compounds against human colon cancer cell line HCT-116 was measured by MTT method.The results indicated that most of the compounds displayed weak MNK inhibitory activity.Among them,compound 8r showed the most potent MNK inhibitory activity with an inhibitory rate of 64％and 59％at 1 µmol·L-1 against MNK1 and MNK2,respectively.The antiproliferation activity demonstrated that 8h,8o,8r,8u and 8w displayed moderate inhibitory activities against HCT-116 cell line with GI50 values of 9.68-13.06 μmo1·L-1.
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